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Synthesis method of key intermediate of beprost sodium

A technology of beraprost sodium and its intermediates, which is applied in the field of compound preparation and can solve the problems of severe exothermic post-processing and difficulties

Inactive Publication Date: 2020-02-04
JINAN KANGHE MEDICAL TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the prior art report, lithium aluminum hydride was used as the reducing agent for the synthesis of intermediate III. This reagent is flammable and explosive. It will exotherm violently during the reaction and the post-processing is difficult, which will bring great limitations to future industrial production.

Method used

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  • Synthesis method of key intermediate of beprost sodium
  • Synthesis method of key intermediate of beprost sodium
  • Synthesis method of key intermediate of beprost sodium

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0077] Embodiment one: the synthesis of intermediate II (R 1 is methyl, R 2 bit TBDMS)

[0078]

[0079] Add 3a,8b-cis-dihydro-3H-5-carboxy-7-dibromocyclopentadiene[b]benzofuran (28 g), acetic acid, paraformaldehyde, concentrated sulfuric acid, and The mass ratio to raw materials is 10:1, the molar ratio of paraformaldehyde to raw materials is 1:1, the molar ratio of concentrated sulfuric acid to raw materials is 2:1, and the system is reacted for 6 hours at 75-80°C under nitrogen atmosphere. Most of the acetic acid was distilled off under reduced pressure, and an aqueous sodium carbonate solution was slowly added to the system. After the bubbles were completely released, the aqueous phase was extracted twice with ethyl acetate, and the ethyl acetate layers were combined, dried, filtered, and the organic phase was rotary evaporated to obtain the crude product ( 1S,2R,3aS,8bS)-2-Acetoxy-1-(acetoxymethyl)-7-bromo-2,3,3a,8b-tetrahydro-1H-cyclopentadiene[b] Benzofuran-5-carb...

Embodiment 2

[0082] Embodiment two: the synthesis of intermediate II (R 1 is methyl, R 2 bit TBDMS)

[0083]

[0084] Add 3a,8b-cis-dihydro-3H-5-carboxy-7-dibromocyclopentadiene[b]benzofuran (28 g), acetic acid, paraformaldehyde, concentrated sulfuric acid, and The mass ratio to raw materials is 4:1, the molar ratio of paraformaldehyde to raw materials is 2:1, the molar ratio of concentrated sulfuric acid to raw materials is 2:1, and the system is reacted for 4 hours at 85-90°C under nitrogen atmosphere. Most of the acetic acid was distilled off under reduced pressure, and an aqueous sodium carbonate solution was slowly added to the system. After the bubbles were completely released, the aqueous phase was extracted twice with ethyl acetate, and the ethyl acetate layers were combined, dried, filtered, and the organic phase was rotary evaporated to obtain the crude product ( 1S,2R,3aS,8bS)-2-Acetoxy-1-(acetoxymethyl)-7-bromo-2,3,3a,8b-tetrahydro-1H-cyclopentadiene[b] Benzofuran-5-carbo...

Embodiment 3

[0087] Embodiment three: the synthesis of intermediate II (R 1 is methyl, R 2 bit TBDMS)

[0088]

[0089] Add 3a,8b-cis-dihydro-3H-5-carboxy-7-dibromocyclopentadiene[b]benzofuran (28 g), acetic acid, paraformaldehyde, concentrated sulfuric acid, and The mass ratio to raw materials is 8:1, the molar ratio of paraformaldehyde to raw materials is 2:1, the molar ratio of concentrated sulfuric acid to raw materials is 3:1, and the system is reacted at 75-80°C for 8 hours under nitrogen atmosphere. Most of the acetic acid was distilled off under reduced pressure, and an aqueous sodium carbonate solution was slowly added to the system. After the bubbles were completely released, the aqueous phase was extracted twice with ethyl acetate, and the ethyl acetate layers were combined, dried, filtered, and the organic phase was rotary evaporated to obtain the crude product ( 1S,2R,3aS,8bS)-2-Acetoxy-1-(acetoxymethyl)-7-bromo-2,3,3a,8b-tetrahydro-1H-cyclopentadiene[b] Benzofuran-5-car...

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Abstract

The invention relates to a synthesis method and application of key intermediate III of beproprost sodium. 3a,8b-cis-dihydro-3H-5-carboxy-7-dibromocyclopentadiene[b]benzofuran is adopted and subjectedto 3-step continuous reaction of princeton reaction, carboxyl esterification and hydroxy protection, and intermediate II is obtained; the ester group of the intermediate II is then reduced with borohydride, and intermediate III is obtained; and the reaction steps are shortened, a product is purified without a column chromatography method, the amount of the three wastes is small, and enlargement iseasy. The mild reducing reagent of borohydride is used for reducing the ester group, the operation is safe, the reaction yield is stable, and industrial production is easy. The intermediate III can be directly used in the synthesis of beprost sodium.

Description

technical field [0001] This field belongs to the field of compound preparation, and specifically relates to a synthetic method of a key intermediate of beraprost sodium. [0002] technical background [0003] Beraprost sodium (trade name Dorner) belongs to prostacyclin derivatives and is an antiplatelet drug developed by Japan Toray Co., Ltd. (Toray). Beraprost (Beraprost) was approved in Japan in 1992 as a drug for chronic arterial occlusion. Beraprost in the form of racemate for the treatment of pulmonary arterial hypertension (PAH) has been approved by the U.S. FDA to enter phase II clinical trials. In 2007, Toray and Astellas (formerly Yamanouchi) )’s Beraprost Sodium Sustained Release Tablets (Careload LA) was approved in Japan for the treatment of PAH, becoming the first sustained release agent among prostacyclins. [0004] [0005] The synthesis process of the beraprost sodium bulk drug involves 9-10 synthesis steps, and the total yield is less than 1%. In partic...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F7/18C07D307/77
CPCC07F7/188C07D307/77C07B2200/07
Inventor 侯云艳艾雷锋范岩森邓超张颖周云志
Owner JINAN KANGHE MEDICAL TECH
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